Vertebrates possess the ability to mount an immune response as a defense against pathogens from the environment as well as against aberrant cells, such as tumor cells, which develop internally. This can take the form of innate immunity, which is mediated by NK cells, neutrophils, and cells of the monocyte/macrophage lineage, or the form of acquired or active immunity against specific antigens, which is mediated by lymphocytes. Active immune responses can be further subdivided into two arms, the humoral response, which entails the production of specific antibodies that serve to neutralize antigens exposed to the systemic circulation and aid in their uptake by professional phagocytic cells, and the cellular arm, which is responsible for the recognition of infected or aberrant cells within the body. Often these immunogenic responses result in diseases and disorders that cause harm to the organism itself. Such disorders are associated with the recognition of self proteins and cells as foreign, and thus trigger an attack upon such cells or self proteins. Common autoimmune disorders include, for example, psoriasis, arthritis, lupus, diabetes, and other medical conditions known in the art.
One of most likely scenarios regarding the pathogenesis of an autoimmune disease such as type I diabetes or multiple sclerosis (MS), for example, may begin with abnormal regulation of autoreactive T cells either due to bystander activation or due to molecular mimicry. For example, a viral infection or exposure to a superantigen may provide sufficient co-stimulation resulting in activation of a few low affinity autoreactive T cells that escape selection in the thymus. Abnormal down-regulation of such autoreactive responses may lead to expansion of pathogenic T cells that infiltrate the organ where the recognized antigen is present. A few host-related factors facilitate the transition between non-pathogenic autoreactivity and autoimmune disease: leaky central negative selection allowing the escape of higher numbers of autoreactive precursors; impaired peripheral tolerance due to abnormalities involving receptors or ligands that mediate down-regulation of lymphocyte activity; a bias to generate TH1 pro-inflammatory responses as opposed to more balanced TH1/TH2 responses; and high frequency and abnormal activity of professional antigen presenting cells (APCs).
Local inflammation and direct destruction of host cells trigger antigen release, uptake by professional APCs, and presentation to specific T cells, thereby perpetuating a positive feed-back that exacerbates the autoimmunity. Simultaneously, normally cryptic, organ-associated antigens may become exposed in the context of activation of professional antigen presenting cells and antigen release, resulting in activation of T cells specific for these other self antigens. Particularly in conditions favoring overall TH1/TH2 imbalance, the employment of additional specificities may accelerate the disease. It is widely believed that whereas TH1 cytokines contribute to the pathogenesis of autoimmunity, TH2 cytokines, on the other hand, may suppress the activity of pathogenic TH1 or Tc1 cells.
Heat shock proteins (hsps) are highly conserved proteins that play an important role in various cellular processes. Hsps are stress proteins that are typically upregulated during cellular stress. Apart from that, it has been shown that hsps are immunodominant. Unique qualities of hsps (e.g., evolutionary conservation, immunodominance, and upregulation during stress) have made hsps attractive candidates as targets for immunotherapy and vaccines. Indeed, at present, the role of immune reactivity to hsps has been proposed in different disease models, varying from cancer to infectious diseases and autoimmune diseases.
Most evidence for the role of hsps in the immune regulation of inflammatory diseases comes from models of chronic arthritis. This research has shown that immunization with hsp10, hsp60, and hsp70 can all confer protection in virtually all models of experimental arthritis. In the model of adjuvant arthritis, immune reactivity to hsps plays a role both in the induction of disease and in protection from disease. For example, on one hand, it was shown that adjuvant arthritis can be induced by means of a T cell clone, called A2b, that is specific for mycobacterial hsp60 180-188 peptide, while on the other hand, later studies showed that preimmunization with mycobacterial hsp60 can effectively protect against disease induction. However, after immunization with hsp60 several epitopes were found to be recognized by the immune system. Interestingly, only one epitope (i.e., a peptide made up of mycobacterial hsp60 residues 256-270) out of eight epitopes was found to be capable to induce protection. This protection was based on the induction of (self-hsp) cross-reactive T cells. Thus there arose a picture from the data of the animal model of adjuvant arthritis for an important role for immune reactivity against hsps in the regulation of arthritis, both in protection and in disease induction. The fact that different epitopes had completely opposite effects underlined the importance of also defining peptide T cell epitopes in the human system.
Over the last 10 years it has become clear that immune reactivity to hsps also plays a crucial role in human chronic arthritis, namely Juvenile Idiopathic Arthritis (JIA) and Rheumatoid Arthritis (RA). First, increased expression of hsp60 was detected in synovial lining cells of subjects with JIA and RA. Secondly, T cell reactivity to both self and non-self hsp60 was found in both diseases. Similarly, immune reactivity to other hsps such as hsp70 and DnaJ was detected in subjects with JIA and RA. In children with JIA, immune reactivity to self-hsp60 seemed predictive of a favorable prognosis.